Diabetes is a metabolic disorder with recurrent or persistent hyperglycemia. Abnormal levels of blood glucose can lead to serious and chronic complications, including cardiovascular disease, chronic renal failure, retinal damage, nerve damage, microvascular damage and obesity.
In the early stage of diabetes treatment, control of diet and exercise therapy are the preferred method for controlling blood glucose. When control of blood glucose is difficult to achieve with these methods, insulin or oral hypoglycemic drugs are needed for the treatment. There have been a variety of hypoglycemic drugs used currently in clinical treatment, including biguanide compounds, sulfonylurea compounds, insulin resistance improving agents, α-glucosidase inhibitors and the likes. However, these drugs are unable to meet the needs of long-term treatment due to various toxic effects. For example, biguanide compounds can cause lactic acidosis; sulfonylurea compounds can lead to hypoglycemia; insulin resistance improving agents can induce edema and heart failure; and α-glucosidase inhibitors can cause symptoms such as abdominal pain, distention, diarrhea and the likes. In consideration of the above situation, it is necessary to develop a safer and more effective novel anti-diabetic drugs to meet the needs of diabetes treatment.
It has been found that the regulation of glucose transport in cells is mainly achieved by the two protein family members of glucose transporters (GLUTS) (passive transport) and sodium-dependent glucose co-transporters (SGLTs) (active transport). The SGLTs family members with glucose transport function are mainly located in the intestine and the proximal tubule of the kidney and the like. Accordingly, it can be inferred that the SGLTs family members play a key role in glucose absorption in the intestine and glucose reuptake in the kidney; and they have become one of the ideal potential targets for treating diabetes.
In particular, family member SGLT-1 protein is mainly located in the intestinal mucosal cells of the small intestine, with less expression in cardiac muscle and the kidney. It mainly cooperates with GLUTs protein to regulate glucose absorption in the intestine. Another family member SGLT-2 protein is mainly responsible for regulating glucose reuptake in the kidneys due to its high level of expression in the kidneys, when glucose in urine passes through the glomerulus, it can actively attach to the epithelial cells of the renal tubule and be transported into the cells by SGLT-2 and recycled. During this process, SGLT-2 is responsible for 90% of the reabsorption, and the remaining 10% of the reabsorption is done by SGLT-1. The theory of SGLT-2 as a major transporter protein has been further confirmed in animal tests. SGLT-2 mRNA level in rat renal cortex cells is reduced by specific SGLT-2 antisense oligonucleotides, thereby significantly inhibiting the reuptake of glucose in rat kidney. Based on these findings, it can be inferred that if a SGLTs (SGLT-1/SGLT-2) inhibitor is developed, through the regulation of its glucose transport function, it is possible to control intestinal absorption of glucose on the one hand, and on the other hand, to inhibit the reuptake of renal glucose and enhance discharge of glucose from the urine, thereby achieving a more systematic hypoglycemic effect, and becoming an ideal drug for treating diabetes.
Additionally, it has been also found that the SGLTs inhibitor can be useful in the treatment of diabetes-related complications, such as retinopathy, neuropathy, nephropathy, insulin resistance caused by glucose metabolism disorders, hyperinsulinemia, hyperlipidemia, obesity and the like. SGLTs inhibitor can also be combined with the existing therapeutic agents, such as sulfonamides, thiazolidinediones, metformin, insulin and the like, which can reduce the dosage of drugs without affecting the efficacy, so as to avoid or reduce the occurrence of adverse effects and improve the compliance of patients to the treatment.
In summary, as a novel drug for treating diabetes, the SGLTs inhibitor has a good development prospects. Therefore, there is an urgent need to develop an effective compound that is safe and has good pharmacokinetic properties for the treatment of diabetes and related metabolic disorders. The patent application WO2015/032272A1 filed by Jiangsu Hansoh Pharmaceuticals Co., Ltd. in 2015 discloses a series of compounds that inhibit sodium-dependent glucose co-transporter (SGLT), wherein the most representative compound of formula (I) is as follows:
The chemical name thereof is: (1S,2S,3S,4R,5S)-5-(3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol. This compound has a very significant inhibitory effect on SGLT2, and also has a significant inhibitory effect on SGLT1, therefore it is expected to be developed as a single inhibitor of SGLT2 or a dual inhibitor of SGLT2/SGLT1. However, this series of compounds are generally in the form of oil or foamy solid due to their structure property, and the skilled person failed to obtain an appropriate aggregation state during the process of drug development. Example 9 of the patent application WO2015/032272A1 merely discloses the compound of formula (I) in an amorphous form, the X-ray powder diffraction pattern thereof is shown in FIG. 8. The impurities contained therein are also difficult to remove by purification. Therefore, there is an urgent need to develop an aggregation form suitable for drug development, so as to meet the requirement of pharmaceutical formulation for clinical research and marketing.